Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker

Jing Tang; Ha T. Do; Andrew D. Huber; Mary C. Casey; Karen A. Kirby; Daniel J. Wilson; Jayakanth Kankanala; Michael A. Parniak; Stefan G. Sarafianos; Zhengqiang Wang

doi:10.1016/j.ejmech.2019.01.081

Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker

Jing Tang
, Ha T. Do
, Andrew D. Huber
, Mary C. Casey
, Karen A. Kirby
, Daniel J. Wilson
, Jayakanth Kankanala
, Michael A. Parniak
, Stefan G. Sarafianos
, Zhengqiang Wang

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low μM, and no to marginal RT polymerase (pol) inhibition up to 10 μM. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors.

Original language	English (US)
Pages (from-to)	390-399
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	166
DOIs	https://doi.org/10.1016/j.ejmech.2019.01.081
State	Published - Mar 15 2019

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health (AI100890 to SGS, MAP and ZW) and partially by the Center for Drug Design, University of Minnesota.

Funding Information:
This research was supported by the National Institutes of Health ( AI100890 to SGS, MAP and ZW) and partially by the Center for Drug Design, University of Minnesota .

Publisher Copyright:
© 2019 Elsevier Masson SAS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

3-Hydroxypyrimidine-2,4-dione (HPD)
Human immunodeficiency virus (HIV)
Inhibitors
Reverse transcriptase (RT)
RNase H

PubMed: MeSH publication types

Journal Article

Publisher link

10.1016/j.ejmech.2019.01.081

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459026

Find It

Find It at U of M Libraries

Cite this

Tang, J., Do, H. T., Huber, A. D., Casey, M. C., Kirby, K. A., Wilson, D. J., Kankanala, J., Parniak, M. A., Sarafianos, S. G., & Wang, Z. (2019). Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker. European Journal of Medicinal Chemistry, 166, 390-399. https://doi.org/10.1016/j.ejmech.2019.01.081

Tang, J, Do, HT, Huber, AD, Casey, MC, Kirby, KA, Wilson, DJ, Kankanala, J, Parniak, MA, Sarafianos, SG & Wang, Z 2019, 'Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker', European Journal of Medicinal Chemistry, vol. 166, pp. 390-399. https://doi.org/10.1016/j.ejmech.2019.01.081

@article{afa6c7bd176f47c59d1daa1668f0e9f8,

title = "Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker",

abstract = "The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low μM, and no to marginal RT polymerase (pol) inhibition up to 10 μM. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors.",

keywords = "3-Hydroxypyrimidine-2,4-dione (HPD), Human immunodeficiency virus (HIV), Inhibitors, Reverse transcriptase (RT), RNase H",

author = "Jing Tang and Do, \{Ha T.\} and Huber, \{Andrew D.\} and Casey, \{Mary C.\} and Kirby, \{Karen A.\} and Wilson, \{Daniel J.\} and Jayakanth Kankanala and Parniak, \{Michael A.\} and Sarafianos, \{Stefan G.\} and Zhengqiang Wang",

note = "Funding Information: This research was supported by the National Institutes of Health (AI100890 to SGS, MAP and ZW) and partially by the Center for Drug Design, University of Minnesota. Funding Information: This research was supported by the National Institutes of Health ( AI100890 to SGS, MAP and ZW) and partially by the Center for Drug Design, University of Minnesota . Publisher Copyright: {\textcopyright} 2019 Elsevier Masson SAS",

year = "2019",

month = mar,

day = "15",

doi = "10.1016/j.ejmech.2019.01.081",

language = "English (US)",

volume = "166",

pages = "390--399",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

}

TY - JOUR

T1 - Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H

T2 - Tolerance of a nonflexible linker

AU - Tang, Jing

AU - Do, Ha T.

AU - Huber, Andrew D.

AU - Casey, Mary C.

AU - Kirby, Karen A.

AU - Wilson, Daniel J.

AU - Kankanala, Jayakanth

AU - Parniak, Michael A.

AU - Sarafianos, Stefan G.

AU - Wang, Zhengqiang

N1 - Funding Information: This research was supported by the National Institutes of Health (AI100890 to SGS, MAP and ZW) and partially by the Center for Drug Design, University of Minnesota. Funding Information: This research was supported by the National Institutes of Health ( AI100890 to SGS, MAP and ZW) and partially by the Center for Drug Design, University of Minnesota . Publisher Copyright: © 2019 Elsevier Masson SAS

PY - 2019/3/15

Y1 - 2019/3/15

N2 - The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low μM, and no to marginal RT polymerase (pol) inhibition up to 10 μM. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors.

AB - The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low μM, and no to marginal RT polymerase (pol) inhibition up to 10 μM. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors.

KW - 3-Hydroxypyrimidine-2,4-dione (HPD)

KW - Human immunodeficiency virus (HIV)

KW - Inhibitors

KW - Reverse transcriptase (RT)

KW - RNase H

UR - https://www.scopus.com/pages/publications/85061102032

UR - https://www.scopus.com/pages/publications/85061102032#tab=citedBy

U2 - 10.1016/j.ejmech.2019.01.081

DO - 10.1016/j.ejmech.2019.01.081

M3 - Article

C2 - 30739822

AN - SCOPUS:85061102032

SN - 0223-5234

VL - 166

SP - 390

EP - 399

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker

Abstract

Bibliographical note

UN SDGs

Keywords

PubMed: MeSH publication types

Publisher link

Find It

Other files and links

Fingerprint

Cite this